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Journal of the American Chemical Society May 2024Nature employs sophisticated mechanisms to precisely regulate self-assembly and functions within biological systems, exemplified by the formation of cytoskeletal...
Nature employs sophisticated mechanisms to precisely regulate self-assembly and functions within biological systems, exemplified by the formation of cytoskeletal filaments. Various enzymatic reactions and auxiliary proteins couple with the self-assembly process, meticulously regulating the length and functions of resulting macromolecular structures. In this context, we present a bioinspired, reaction-coupled approach for the controlled supramolecular polymerization in synthetic systems. To achieve this, we employ an enzymatic reaction that interfaces with the adenosine triphosphate (ATP)-templated supramolecular polymerization of naphthalene diimide monomers (). Notably, the enzymatic production of ATP (template) plays a pivotal role in facilitating reaction-controlled, cooperative growth of the monomers. This growth process, in turn, provides positive feedback to the enzymatic production of ATP, creating an ideal reaction-coupled assembly process. The success of this approach is further evident in the living-growth characteristic observed during seeding experiments, marking this method as the pioneering instance where reaction-coupled self-assembly precisely controls the growth kinetics and structural aspects of supramolecular polymers in a predictive manner, akin to biological systems.
Topics: Polymerization; Naphthalenes; Adenosine Triphosphate; Imides; Macromolecular Substances; Molecular Structure; Kinetics; Polymers
PubMed: 38747446
DOI: 10.1021/jacs.4c03588 -
The Journal of Biological Chemistry Sep 2023The hydrolysis of ATP is the primary source of metabolic energy for eukaryotic cells. Under physiological conditions, cells generally produce more than sufficient levels... (Review)
Review
The hydrolysis of ATP is the primary source of metabolic energy for eukaryotic cells. Under physiological conditions, cells generally produce more than sufficient levels of ATP to fuel the active biological processes necessary to maintain homeostasis. However, mechanisms underpinning the distribution of ATP to subcellular microenvironments with high local demand remain poorly understood. Intracellular distribution of ATP in normal physiological conditions has been proposed to rely on passive diffusion across concentration gradients generated by ATP producing systems such as the mitochondria and the glycolytic pathway. However, subcellular microenvironments can develop with ATP deficiency due to increases in local ATP consumption. Alternatively, ATP production can be reduced during bioenergetic stress during hypoxia. Mammalian cells therefore need to have the capacity to alter their metabolism and energy distribution strategies to compensate for local ATP deficits while also controlling ATP production. It is highly likely that satisfying the bioenergetic requirements of the cell involves the regulated distribution of ATP producing systems to areas of high ATP demand within the cell. Recently, the distribution (both spatially and temporally) of ATP-producing systems has become an area of intense investigation. Here, we review what is known (and unknown) about intracellular energy production and distribution and explore potential mechanisms through which this targeted distribution can be altered in hypoxia, with the aim of stimulating investigation in this important, yet poorly understood field of research.
Topics: Animals; Humans; Adenosine Triphosphate; Energy Metabolism; Mitochondria; Cell Hypoxia; Adaptation, Physiological
PubMed: 37507013
DOI: 10.1016/j.jbc.2023.105103 -
Biological Chemistry Sep 2023ATP is an important small molecule that appears at outstandingly high concentration within the cellular medium. Apart from its use as a source of energy and a... (Review)
Review
ATP is an important small molecule that appears at outstandingly high concentration within the cellular medium. Apart from its use as a source of energy and a metabolite, there is increasing evidence for important functions as a cosolute for biomolecular processes. Owned to its solubilizing kosmotropic triphosphate and hydrophobic adenine moieties, ATP is a versatile cosolute that can interact with biomolecules in various ways. We here use three models to categorize these interactions and apply them to review recent studies. We focus on the impact of ATP on biomolecular solubility, folding stability and phase transitions. This leads us to possible implications and therapeutic interventions in neurodegenerative diseases.
Topics: Solubility; Adenosine Triphosphate
PubMed: 37656203
DOI: 10.1515/hsz-2023-0202 -
Plant Communications Apr 2024ATP is the primary form of energy for plants, and a shortage of cellular ATP is generally acknowledged to pose a threat to plant growth and development, stress... (Review)
Review
ATP is the primary form of energy for plants, and a shortage of cellular ATP is generally acknowledged to pose a threat to plant growth and development, stress resistance, and crop quality. The overall metabolic processes that contribute to the ATP pool, from production, dissipation, and transport to elimination, have been studied extensively. Considerable evidence has revealed that in addition to its role in energy supply, ATP also acts as a regulatory signaling molecule to activate global metabolic responses. Identification of the eATP receptor DORN1 contributed to a better understanding of how plants cope with disruption of ATP homeostasis and of the key points at which ATP signaling pathways intersect in cells or whole organisms. The functions of SnRK1α, the master regulator of the energy management network, in restoring the equilibrium of the ATP pool have been demonstrated, and the vast and complex metabolic network mediated by SnRK1α to adapt to fluctuating environments has been characterized. This paper reviews recent advances in understanding the regulatory control of the cellular ATP pool and discusses possible interactions among key regulators of ATP-pool homeostasis and crosstalk between iATP/eATP signaling pathways. Perception of ATP deficit and modulation of cellular ATP homeostasis mediated by SnRK1α in plants are discussed at the physiological and molecular levels. Finally, we suggest future research directions for modulation of plant cellular ATP homeostasis.
Topics: Arabidopsis; Arabidopsis Proteins; Adenosine Triphosphate; Signal Transduction; Homeostasis
PubMed: 38327057
DOI: 10.1016/j.xplc.2024.100834 -
The EMBO Journal Aug 2023Mycobacteria, such as Mycobacterium tuberculosis, depend on the activity of adenosine triphosphate (ATP) synthase for growth. The diarylquinoline bedaquiline (BDQ), a...
Mycobacteria, such as Mycobacterium tuberculosis, depend on the activity of adenosine triphosphate (ATP) synthase for growth. The diarylquinoline bedaquiline (BDQ), a mycobacterial ATP synthase inhibitor, is an important medication for treatment of drug-resistant tuberculosis but suffers from off-target effects and is susceptible to resistance mutations. Consequently, both new and improved mycobacterial ATP synthase inhibitors are needed. We used electron cryomicroscopy and biochemical assays to study the interaction of Mycobacterium smegmatis ATP synthase with the second generation diarylquinoline TBAJ-876 and the squaramide inhibitor SQ31f. The aryl groups of TBAJ-876 improve binding compared with BDQ, while SQ31f, which blocks ATP synthesis ~10 times more potently than ATP hydrolysis, binds a previously unknown site in the enzyme's proton-conducting channel. Remarkably, BDQ, TBAJ-876, and SQ31f all induce similar conformational changes in ATP synthase, suggesting that the resulting conformation is particularly suited for drug binding. Further, high concentrations of the diarylquinolines uncouple the transmembrane proton motive force while for SQ31f they do not, which may explain why high concentrations of diarylquinolines, but not SQ31f, have been reported to kill mycobacteria.
Topics: Diarylquinolines; Antitubercular Agents; Adenosine Triphosphate; Mycobacterium tuberculosis
PubMed: 37377118
DOI: 10.15252/embj.2023113687 -
Circulation Dec 2023
Topics: Humans; Stroke Volume; Heart Failure; Myocardium; Adenosine Triphosphate; Energy Metabolism
PubMed: 38079486
DOI: 10.1161/CIRCULATIONAHA.123.065217 -
Frontiers in Immunology 2023Creatine is an indispensable organic compound utilized in physiological environments; however, its role in immunity is still poorly understood. Here, we show that...
Creatine is an indispensable organic compound utilized in physiological environments; however, its role in immunity is still poorly understood. Here, we show that creatine supplementation enhances anti-tumor immunity through the functional upregulation of macrophages by increasing adenosine triphosphate (ATP) production. Creatine supplementation significantly suppressed B16-F10-originated tumor growth in mice compared with the control treatment. Under these conditions, intratumor macrophages polarized towards the M1 phenotype rather than the M2 phenotype, and there was an increase in tumor antigen-specific CD8+ T cells in the mice. The cytokine production and antigen-presenting activity in the macrophages were enhanced by creatine supplementation, resulting in a substantial increase in tumor antigen-specific CD8+ T cells. ATP upregulation was achieved through the cytosolic phosphocreatine (PCr) system via extracellular creatine uptake, rather than through glycolysis and mitochondrial oxidative phosphorylation in the macrophages. Blockade of the creatine transporter (CrT) failed to upregulate ATP and enhance the immunological activity of macrophages in creatine supplementation, which also impaired CD8+ T cell activity. Consequently, CrT blockade failed to suppress tumor growth in the creatine-supplemented mice. Thus, creatine is an important nutrient that promotes macrophage function by increasing ATP levels, ultimately contributing to enhanced anti-tumor immunity orchestrated by CD8+ T cells.
Topics: Animals; Mice; Creatine; Adenosine Triphosphate; Macrophages; Antigens, Neoplasm; Dietary Supplements
PubMed: 37662917
DOI: 10.3389/fimmu.2023.1176956 -
Extracellular adenosine triphosphate regulates inflammatory responses of periodontal ligament cells.Journal of Periodontology Mar 2024Various stimuli, that is, mechanical stresses or inflammation, induce the release of adenosine triphosphate (ATP) by human periodontal ligament cells (HPDLCs)....
BACKGROUND
Various stimuli, that is, mechanical stresses or inflammation, induce the release of adenosine triphosphate (ATP) by human periodontal ligament cells (HPDLCs). Extracellular adenosine triphosphate (eATP) affects HPDLCs' functions such as immunosuppressive action and inflammatory responses. Lipopolysaccharide (LPS) is the key factor involved in periodontal inflammation. However, the possible correlation and detailed mechanism of inflammation-mediated eATP by LPS and inflammatory cascade formation in HPDLCs is unclarified. This study aims to examine the role of eATP on the HPDLCs' responses concerning inflammatory actions after LPS treatment.
METHODS
HPDLCs were stimulated with Porphyromonas gingivalis LPS and polyinosinic:polycytidylic acid (poly I:C). The amount of ATP release was measured at different time points using a bioluminescence assay. HPDLCs were treated with eATP. The expression of pro-inflammatory and anti-inflammatory genes was determined. Specific PX purinoreceptor 7 (PX) inhibitors (brilliant blue G [BBG] and KN62), a specific PY purinoreceptor 1 (PY) inhibitors (MRS2179), calcium chelator (EGTA), protein kinase C (PKC) inhibitors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF𝜅B) activation inhibitors, and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) inhibitors (H89 dihydrochloride) and activators (forskolin) were used to dissect the mechanism of eATP-induced HPDLCs' inflammatory responses.
RESULTS
LPS and poly I:C induced ATP release. A low concentration of eATP (50 µM) increased pro-inflammatory genes (COX2, IL1B, IL6, IL8, IL12, and TNFA), while a high concentration (500 µM) enhanced anti-inflammatory genes (IL4 and IL10). BBG, KN62, and NF𝜅B activation inhibitors impeded eATP-induced pro-inflammatory genes. MRS2179 and H89 markedly suppressed eATP-induced anti-inflammatory genes. Forskolin induced IL4 and IL10.
CONCLUSION
HPDLCs respond to LPS by releasing ATP. eATP has dose-dependent dual functions on HPDLCs' inflammatory responses via different pathways. As regulation of inflammation is important in regeneration, eATP may help to limit inflammation and trigger periodontal regeneration.
Topics: Humans; Periodontal Ligament; Adenosine Triphosphate; Lipopolysaccharides; Colforsin; Interleukin-10; Interleukin-4; Inflammation; Anti-Inflammatory Agents; Cells, Cultured; Poly I; Isoquinolines; Sulfonamides
PubMed: 37932872
DOI: 10.1002/JPER.23-0389 -
Cutaneous and Ocular Toxicology Sep 2023This study aims to investigate possible preventive effect of ATP on optic nerve damage caused by amiodarone in rats.
OBJECTIVE
This study aims to investigate possible preventive effect of ATP on optic nerve damage caused by amiodarone in rats.
MATERIAL AND METHOD
Thirty albino male Wistar rats weighing between 265 and 278 g were used in the study. Before the experiment, the rats were housed at 22 °C in a 12-h light/dark cycle under appropriate condition. The rats were equally divided into five groups of six animals each: healthy group, 50 mg/kg amiodarone (AMD-50), 100 mg/kg amiodarone (AMD-100), 25 mg/kg ATP + 50 mg/kg amiodarone (ATAD-50), and 25 mg/kg ATP + 100 mg/kg amiodarone (ATAD-100). At the end of 14th day, the animals were sacrificed using cardiac puncture under deep thiopental anaesthesia, and optic nerve tissues were harvested to measure superoxide dismutase (SOD), total glutathione (tGSH), malondialdehyde (MDA), and catalase (CAT) levels.
RESULTS
The MDA levels were found to be significantly higher in the AMD-50 and AMD-100 groups compared to the healthy group ( ˂ 0.001). There was also a significant difference between the AMD-50 and ATAD-50 groups, and between the AMD-100 and ATAD-100 groups regarding MDA levels ( ˂ 0.001). tGSH, SOD, and CAT levels were significantly lower in the AMD-50 and AMD-100 groups compared to the healthy group ( ˂ 0.001). ATP was found to partially inhibit amiodarone-induced optic neuropathy.
CONCLUSION
The biochemical and histopathological results of this study demonstrated that amiodarone at high doses caused more severe optic neuropathy inducing oxidative damage, but ATP could relatively antagonise these negative effects on the optic nerve. Therefore, we believe that ATP may be beneficial in preventing amiodarone-induced optic neuropathy.
Topics: Rats; Animals; Amiodarone; Rats, Wistar; Adenosine Triphosphate; Optic Nerve Diseases; Optic Nerve; Glutathione; Superoxide Dismutase
PubMed: 37335833
DOI: 10.1080/15569527.2023.2227265 -
Science Advances Oct 2023Endoplasmic reticulum-associated degradation (ERAD) maintains protein homeostasis by retrieving misfolded proteins from the endoplasmic reticulum (ER) lumen into the...
Endoplasmic reticulum-associated degradation (ERAD) maintains protein homeostasis by retrieving misfolded proteins from the endoplasmic reticulum (ER) lumen into the cytosol for degradation. The retrotranslocation of misfolded proteins across the ER membrane is an energy-consuming process, with the detailed transportation mechanism still needing clarification. We determined the cryo-EM structures of the hetero-decameric complex formed by the Derlin-1 tetramer and the p97 hexamer. It showed an intriguing asymmetric complex and a putative coordinated squeezing movement in Derlin-1 and p97 parts. With the conformational changes of p97 induced by its ATP hydrolysis activities, the Derlin-1 channel could be torn into a "U" shape with a large opening to the lipidic environment, thereby forming an entry for the substrates in the ER membrane. The EM analysis showed that p97 formed a functional protein complex with Derlin-1, revealing the coupling mechanism between the ERAD retrotranslocation and the ATP hydrolysis activities.
Topics: Humans; Endoplasmic Reticulum-Associated Degradation; Cryoelectron Microscopy; Proteasome Endopeptidase Complex; Membrane Proteins; Adenosine Triphosphatases; Adenosine Triphosphate
PubMed: 37831771
DOI: 10.1126/sciadv.adi5656